Transgenic mice bearing an oncogene whose expression is directed to a specific tissue provide a powerful tool for dissecting neoplasia, as they allow access to the premalignant phase, permit tests of oncogene cooperativity within relevant cell types, and can reveal the influence of genetic background. To explore hematopoietic, particularly lymphoid, neoplasia, we have constructed transgenic lines bearing different oncogenes coupled to an immunoglobulin enhancer [Emu], which promotes expression in T as well as B lymphocytes and, less frequently, in myeloid cells. These lines provide novel animal models for the development of clonal pre-B and B lymphomas [myc and N-myc], plasmacytomas [v-abl], T and pre-B lymphomas [bcr-v-abl], T lymphomas and macrophage tumors [N-ras], as well as excess lymphocyte syndrome [bcl-2]. We plan now to characterize further the neoplastic process in these strains and later in new lines that will include the rel oncogene and the p53 anti- oncogene, both of which have been implicated in hematopoietic malignancies. As well as pathogenesis, we will explore the preneoplastic phase to delineate how each gene affects cell growth and differentiation, giving particular emphasis to the profoundly disturbed lymphoid development in the bcl-2 mice. To identify somatic events that synergise with transgene expression to trigger malignancy in the mice, we will search for alterations to known oncogenes and anti-oncogenes. Oncogene cooperativity will also be explored by infection with onc-bearing retroviruses and by crossing the different Emu-onc strains. Initial crosses suggest that certain oncogene combinations may provide access to new tumor types of remarkably early developmental stages. We are seeking to identify novel oncogenes that cooperate with the transgene by infecting developmental stages. We are seeking to identify novel oncogenes that cooperate with the transgene by infecting the mice with a retrovirus lacking an oncogene and isolating DNA flanking the provirus from rapidly developing tumors. This approach appears to be effective in all strains tested and has already yielded a novel gene, emi-1, which will now be sequenced and assessed for ability to collaborate with myc. Finally, by breeding certain transgenic strains with different inbred strains, we will explore further our evidence that genetic background influences tumorigenicity. SIGNIFICANCE. This highly productive project has already generated unique animal models for defining the pathways to multiple forms of hematopoietic malignancy. The proposed studies should help to reveal how oncogenes influence differentiation and collaborate to elicit malignancy, identify new oncogenes, clarify the role of anti-oncogenes, reveal whether genetic influences can modulate susceptibility and provide tumor lines representing previously inaccessible development stages. The results will be directly relevant to many human lymphomas and leukemias and have wide ramifications for malignancy in general.